NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

Abstract

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-17-003-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/80480; and 3) view/print certificate.

Release date: March 10, 2017; Expiration date: March 10, 2018

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to NCCN Guidelines for CLL/SLL

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for CLL/SLL

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) constitute approximately 7% of newly diagnosed non-Hodgkin's lymphomas (NHL) cases.1 In 2016, an estimated 18,960 people were diagnosed with CLL in the United States and an estimated 4,660 people died of the disease.2 CLL/SLL is characterized by a progressive accumulation of leukemic cells in the blood, bone marrow, and lymphoid tissues.

CLL and SLL are different manifestations of the same disease and are managed in much the same way.3 The major difference between them is that a significant number of the abnormal lymphocytes are found in blood in CLL, in addition to bone marrow and lymphoid tissue; in SLL there are few, if any, abnormal lymphocytes circulating in the blood, and the bulk of disease is in the lymph nodes, bone marrow, and other lymphoid tissues.

During the past several decades, therapeutic options for CLL have evolved significantly. The advent

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

of immunomodulating agents (eg, lenalidomide) and CD20 (rituximab, obinutuzumab, and ofatumumab) and CD52 (alemtuzumab) monoclonal antibodies have led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways (eg, Bruton tyrosine kinase [BTK], phosphatidylinositol 3-kinase [PI3K], and spleen tyrosine kinase) and a small molecule inhibitor of the BCL-2 family of proteins have shown promising activity in the treatment of patients with CLL (Tables 1 and 2).

These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed or refractory CLL/SLL.

First-Line Therapy

First-line therapy with fludarabine/cyclophosphamide/rituximab (FCR) results in high response rates and improved overall survival (OS) in specific subgroups of fit patients with previously untreated CLL, especially those with mutated IGHV.4,5 In a phase II study of 300 patients with previously untreated CLL, at a median follow-up of 12.8 years, the overall response rate (ORR) was 95% (72% achieved a complete response [CR]),4 median progression-free survival (PFS) was 6.4 years, and the overall 12.8-year PFS rate was 30.9% (53.9% for those with mutated IGHV and 8.7% for unmutated IGHV). Minimal residual disease (MRD) negativity was achieved in 50.7% of patients with mutated IGHV, with a PFS rate of 79.8% at 12.8 years. In a multivariable analysis, unmutated IGHV and del(17p) by conventional karyotyping were significantly associated with inferior PFS. Long-term PFS was notable particularly for patients with mutated IGHV, with a plateau on the PFS curve beyond 10 years. In a large, international, randomized, phase III clinical trial (CLL8 study), 817 physically fit patients with previously untreated CLL (median age, 61 years) were randomized to receive

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

up to 6 courses of either FCR (n=408) or fludarabine/cyclophosphamide (FC; n=409).5 The FCR regimen resulted in a higher ORR (90% vs 80%; P<.001) and CR rate (44% vs 22%; P<.001) compared with FC. With a median follow-up of 5.9 years, the median PFS was 56.8 months for FCR and 33 months for FC (P<.001); median OS was not reached for FCR and was 86.0 months for FC (P=.001).5 FCR was associated with a statistically significant survival benefit compared with FC in patients aged <65 years (5-year OS, 80.9% and 69.2%, respectively; P=.002); corresponding 5-year OS rates were 73.9% and 61.6%, respectively (P=.288). The incidence of prolonged neutropenia was significantly higher with the FCR regimen than with FC during the first year after treatment (16.6% vs 8.8%; P=.007).

Bendamustine, an alkylating agent with a low cross-resistance to other alkylating agents, was evaluated as first-line monotherapy and in combination with rituximab.68 In a multicenter phase II trial (CLL2M study), bendamustine/rituximab (BR) resulted in high ORR rates (88%; CR, 23%) in previously untreated patients (n=117; 26% were aged >70 years), with similar response and survival outcomes among the subgroup of elderly patients (aged >70 years).6 After a median follow-up of 27 months, median PFS was 34 months and the OS rate was 90.5%. Thrombocytopenia (22%), neutropenia (20%), anemia (20%), allergic/infusion reactions (9%), and infections (8%) were the most common grade 3 or 4 toxicities.

The final analysis of the CLL10 study, which compared BR with FCR as first-line therapy for CLL in fit patients without del(17p) (n=567; Cumulative illness Rating Scale [CIRS] score ≤6, creatinine clearance [CrCl] >70 mL/min), confirmed the superiority in PFS with FCR over BR in patients aged ≤65 years without significant comorbidities.7 The median age was 61.6 years for all patients, but a significantly higher proportion of patients were >65 years in the BR arm (39% vs 30%). After a median follow-up of 37.1 months, the ORR was 95% for FCR and 96%

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

for BR (P=1.0) with no difference in OS (3-year OS rate, 91% vs 92%, respectively; P=.89). FCR resulted in a higher CR rate (40% vs 31%), more MRD negativity (59% vs 26% at 12 months; P<.0001; and 55% vs 27% at 18 months; P=.002), and longer median PFS (55.2 vs 41.7 months; P=.0003) compared with BR. The PFS benefit of FCR was significant in physically fit patients aged <65 years and in those with mutated IGHV; the median PFS was 53.6 and 38.5 months, respectively, for FCR and BR (P=.0004). There was no significant difference in PFS between FCR and BR for patients aged >65 years (median not reached vs 48.5 months, respectively; P=.172). Among patients with mutated IGHV, the median PFS was not reached for FCR compared with 55.4 months for BR (P=.089). The incidence of severe neutropenia and infections were significantly more frequent in the FCR arm (39% vs 25%), especially in those aged >65 years.

Updated results of the study confirmed that BR is also associated with a decreased risk of secondary acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).9 After a median follow-up of 58.2 months, the incidences of secondary AML and MDS were 3% and 1% in the FCR and BR arms, respectively. The results of the study confirm that FCR remains the standard first-line therapy for untreated CLL in fit patients and particularly for those with mutated IGHV. BR is an alternative treatment option for fit elderly patients or those with previous infections.

An ongoing phase III randomized trial is comparing rituximab/chlorambucil (R-chlorambucil) and BR as first- or second-line therapy in patients with CLL who are not candidates for fludarabine-based chemoimmunotherapy due to older age or presence of comorbid conditions.8 In an interim analysis (126 evaluable patients; 58 treated with BR, 68 treated with R-chlorambucil; median age, 74 years; range, 44–91), at the median follow-up of 24 months, the ORR among the patients who received first-line therapy was 91% in the BR group (CR,

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

24%) and 86% (CR, 9%) in the R-chlorambucil group.8 The median PFS was significantly longer in BR group than in the R-chlorambucil group (40 vs 30 months; P=.003), but the median OS was not significantly different (44 months vs not calculable). The incidence of adverse events (AEs) was similar between treatment groups (98% for BR vs 97% for R-chlorambucil), but the incidence of grade 3 AEs was higher for BR compared with R-chlorambucil (75% and 64%, respectively).

Obinutuzumab is a glycoengineered, humanized, type II antibody targeted against CD20. Results of the CLL11 study established obinutuzumab plus chlorambucil as the new standard of care for both elderly patients and those with comorbidities lacking del(17p).10,11 In this study, 781 patients with comorbid conditions (CIRS score >6, or estimated CrCl, 30–69 mL/min) were randomized to receive either chlorambucil (n=118), obinutuzumab plus chlorambucil (n=333), or rituximab plus chlorambucil (n=330).10 Combination obinutuzumab/chlorambucil and rituximab/chlorambucil resulted in a significant improvement in median PFS compared with chlorambucil alone (26.7, 16.3, and 11.1.months, respectively; P<.001).10 The survival benefit was seen in all subgroups except patients with del(17p). After the median observation time of 39.0 months, obinutuzumab/chlorambucil significantly prolonged median PFS (28.7 vs 15.7 months; P<.001), and median time to next treatment (51 vs 38.2 months; P<.0001) compared with rituximab/chlorambucil. There was also a trend toward OS benefit for obinutuzumab.11 The most frequent grade ≥3 toxicities with obinutuzumab/chlorambucil included neutropenia (35%), infusion-related reactions (21%), thrombocytopenia (11%), and infections (11%); neutropenia (28%) and infections (14%) were the most frequent grade ≥3 toxicities associated with rituximab/chlorambucil.

Ofatumumab (a fully human anti-CD20 monoclonal antibody) was evaluated in a multicenter, open-label, phase III study (COMPLEMENT 1) as first-line treatment for patients with untreated CLL

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

who were considered inappropriate for fludarabine-based regimens due to advanced age and/or comorbidities; 447 patients were randomized to ofatumumab/chlorambucil versus chlorambucil monotherapy.12 After a median follow-up of 29 months, the median PFS was significantly longer for ofatumumab/chlorambucil compared with chlorambucil monotherapy (22.4 vs 13.1 months; P<.001)12; median OS was not reached in either arm. Ofatumumab/chlorambucil also resulted in a higher ORR (82% vs 69%; P=.001) and superior CR rate (12% vs 1%) compared with chlorambucil alone.

Ibrutinib, an irreversible inhibitor of BTK initially approved for relapsed or refractory CLL, was also evaluated in patients with untreated CLL/SLL, including those with del(17p).1317 Five-year follow-up data from the multicenter phase Ib/II study, which included 31 patients aged ≥65 years with untreated CLL/SLL, confirmed that ibrutinib induces very durable responses across all subgroups, including those aged ≥65 years with untreated CLL/SLL and those with del(17p), del(11q), or unmutated IGHV.14 After a median follow-up of 5 years, ibrutinib (420 mg) resulted in an ORR of 84% (CR, 29%); median PFS was not reached and the estimated PFS rate at 60 months was 92%. Responses were independent of the presence of high-risk features; however, the number of patients with del(17p), del(11q), trisomy 12, or elevated beta-2-microglobulin was small in this study. In another phase II trial that included 35 treatment-naïve patients with del(17p) treated with ibrutinib (aged ≥18 years; median, 62 years), at a median follow-up of 24 months, ibrutinib resulted in objective responses in 32 of 33 evaluable patients (55% experienced partial response [PR], and 42% experienced a PR with lymphocytosis) and the estimated OS at 24 months was 84%.15 The cumulative incidence of progression at 24 months was 9%. Grade ≥3 neutropenia, anemia, and thrombocytopenia were reported in 24%, 14%, and 10% of patients, respectively;

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

grade 3 pneumonia (6%) and rash (2%) were also reported.

The efficacy and safety of ibrutinib in patients aged ≥65 years with untreated CLL/SLL without del(17p) was demonstrated in a randomized phase III study (RESONATE-2; 269 patients were randomized to receive ibrutinib or chlorambucil as first-line therapy).16 After a median follow-up of 28.6 months, ibrutinib resulted in a significantly higher ORR (92% vs 36%; P<.0001) and significantly longer PFS (89% vs 34% at 24 months; P<.0001) compared with chlorambucil. With 41% of patients switching to ibrutinib, the estimated 2-year OS rates in the intent-to-treat population were 95% and 84% for patients treated with ibrutinib and chlorambucil, respectively.17 Ibrutinib was approved as first-line therapy for all patients, although the efficacy of ibrutinib as first-line therapy in patients aged <65 years without del(17p) has not been established in a randomized clinical trial.

Relapsed or Refractory Therapy

The current standards of care for relapsed or refractory CLL/SLL are ibrutinib, idelalisib, and idelalisib with rituximab and venetoclax for relapsed/refractory del(17p) CLL/SLL (see Table 2).

Ibrutinib has remarkable monotherapy activity with a favorable toxicity profile in patients with relapsed or refractory CLL.1820 In the phase III randomized RESONATE study, 391 patients with previously treated CLL were randomized to monotherapy with ibrutinib (420 mg/d) or ofatumumab.18 Most patients had advanced-stage disease and high-risk features, including del(17p), del(11q), or beta-2-microglobulin (>3.5 mg/L). At a median follow-up of 9.4 months, the ibrutinib group experienced significantly prolonged PFS (median not reached vs 8.1 months for ofatumumab) and OS (HR for death in the ibrutinib group, 0.43; P=.005; 57% reduction in the risk of death). Among patients with del(17p), median PFS was not reached for ibrutinib compared with a median PFS of 5.8 months for ofatumumab.18

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

At 12 months, the OS rate was 91% and 81%, respectively, for ibrutinib and ofatumumab; the ORR was also significantly higher with ibrutinib (42% vs 4%; P<.001). The most frequent nonhematologic AEs were mild (grades 1/2) with diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group, and fatigue, infusion-related reactions, and cough in the ofatumumab group. Updated results of this study also confirmed that ibrutinib significantly improved ORR, PFS, and OS compared with ofatumumab in patients with CLL/SLL who had received ≥1 prior treatment.19 With a median follow-up of 16 months, the ORR (90% vs 25%; P<.0001), median PFS (not reached vs 8.1 months for ofatumumab; P<.0001), and OS rates (18-month OS, 85% and 78%, respectively) were significantly improved for ibrutinib. Results of the phase II RESONATE-17 study further confirmed the safety and efficacy of ibrutinib in 144 patients with relapsed or refractory CLL with del(17p).20 In an extended analysis with a median follow-up of 27.6 months, the investigator-assessed ORR and 24-month PFS and OS rates were 83%, 63%, and 75%, respectively.20

Idelalisib (the isoform-selective oral inhibitor of PI3K-delta) has demonstrated promising clinical activity in phase I–II studies in patients with relapsed or refractory CLL/SLL, both as monotherapy and in combination with rituximab.2123 In the multicenter phase III randomized study, 220 patients with relapsed CLL were randomized to receive rituximab with either idelalisib (150 mg) or placebo.21 Most of the patients (78%) were aged ≥65 years, 40% had moderate renal dysfunction (CrCl, <60 mL/min), 35% had poor bone marrow function (grade ≥3 cytopenias), and 85% had a CIRS score >6. At the first planned interim analysis, the study was stopped early because of the overwhelming efficacy of idelalisib plus rituximab.21 At 24 weeks, the PFS rate was 93% and 46% in the idelalisib and placebo groups, respectively. Among patients with relapsed CLL with coexisting conditions, combination idelalisib/rituximab significantly improved ORR (81% vs 13%;

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

P<.001), PFS (not reached in the idelalisib group vs 5.5 months for placebo), and OS at 12 months (92% vs 80%; P=.02) compared with rituximab plus placebo. Grade 3 or 4 AEs (pneumonia, pyrexia, and febrile neutropenia) were reported in 40% of patients in the idelalisib group and 35% in the placebo group. The second interim analysis of this study also confirmed the superior safety and efficacy of idelalisib plus rituximab in terms of ORR, PFS, and OS.24 The combination also retained efficacy in patients with high-risk features, such as del(17p) or TP53 mutations; unmutated IGHV, ZAP70, and CD38 expression; and beta-2-microglobulin (>4 mg/L).22 A post hoc analysis of 39 patients with relapsed or refractory SLL enrolled in phase I (n=11) and II (n=28) studies (that evaluated the efficacy and safety of patients on idelalisib with relapsed or refractory indolent NHL) showed that idelalisib monotherapy has substantial clinical activity in the subset of patients with relapsed or refractory SLL23: the ORR was 55% (6 of 11) and 61% (17 of 28); median duration of response was 2.3 and 12.5 months; and median PFS was 3.7 and 11.4 months, respectively. Idelalisib monotherapy is approved for the treatment of relapsed SLL in patients who have received ≥2 prior systemic therapies.

Idelalisib in combination with rituximab is approved for the treatment of relapsed CLL in patients for whom rituximab monotherapy would be considered appropriate due to other comorbidities (reduced renal function as measured by CrCl <60 mL/min, or NCI CTCAE grade ≥3 neutropenia or thrombocytopenia resulting from myelotoxic effects of prior treatment with cytotoxic agents). Due to infection-related toxicity and deaths seen in phase III clinical trials with idelalisib in previously untreated CLL, it should not be used in the first line. Prescribers should be aware of this increased risk for infections in patients with relapsed or refractory CLL. Infection prophylaxis for herpes simplex virus, Pneumocystis jirovecii pneumonia (PJP), and routine monitoring for cytomegalovirus (CMV) reactivation are recommended for patients on idelalisib.

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NCCN Guidelines Insights: CLL/SLL, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0030

Venetoclax, a small-molecule BCL2 inhibitor that induces CLL cell apoptosis, has demonstrated activity in relapsed or refractory CLL.25,26 In a phase II study of 107 patients (61 patients aged ≥65 years; 46 patients aged <65 years) with relapsed or refractory del(17p) CLL, at a median follow-up of 12.1 months, venetoclax resulted in an ORR of 79.4% as assessed by the independent review committee.25 Venetoclax resulted in a high ORR (>70%) in all subgroups of patients with additional risk features [eg, fludarabine-refractory status, bulky disease, del(17p), TP53 mutation]; estimated 12-month PFS and OS rates were 72% and 86.7%, respectively. Neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%) were the most common treatment-related AEs. Venetoclax has also shown promising activity in patients with relapsed or refractory CLL who have failed to respond or are intolerant to ibrutinib or idelalisib.26 In a phase II study of 64 patients with relapsed or refractory CLL after prior treatment with ibrutinib (arm A; n=43; 39 patients refractory to ibrutinib) or idelalisib (arm B; n=21; 14 patients refractory to idelalisib), venetoclax resulted in an ORR of 70% (arm A) and 48% (arm B).26 In the subset of patients with CLL refractory to ibrutinib or idelalisib, the ORR was 67% (26 of 39, arm A) and 57% (8 of 14, arm B), respectively. The estimated 12-month PFS and OS rates for all patients were 72% and 90%, respectively; median PFS and OS was not reached at the time of analysis. Neutropenia can be a longer-term toxicity requiring growth factor support and/or venetoclax dose adjustment. Initiation at a lower dose (20 mg for 1 week) and a gradual stepwise ramp-up over 5 weeks to the target dose (400 mg/d) along with prophylaxis for tumor lysis syndrome (TLS) is recommended to mitigate the risk and frequency of TLS in patients receiving venetoclax (see CSLL-G; page 304).25,27

Ofatumumab is approved for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. However, it has demonstrated activity in patients with CLL refractory to fludarabine and

Table 1.

Treatment Options for First-line Therapy

Table 1.
alemtuzumab or in patients for whom alemtuzumab is contraindicated due to bulky lymphadenopathy.28,29 The COMPLEMENT 2 study evaluated FC plus ofatumumab versus FC alone in patients with relapsed CLL (n=365).30 FC plus ofatumumab was associated with improved PFS and a manageable safety profile. Median PFS (primary end point; assessed by the independent review committee) was 28.9 and 18.8 months, respectively, for FC plus ofatumumab versus FC (P=.0032); no significant difference in OS was seen between the treatment arms. The incidences of grade ≥3 AEs were 74% and 69%, respectively, for the 2 treatment groups. Neutropenia was the most common AE reported in 49% of patients treated with FC plus ofatumumab and in 36% treated with FC.

The phase III randomized trial PROLONG evaluated the efficacy and safety of ofatumumab maintenance versus observation in 474 patients with relapsed CLL in CR or PR after second-line or third-line therapy.31 At a median follow-up of 19.1 months, ofatumumab maintenance resulted in improved PFS (29.4 vs 15.2 months, respectively; P<.0001). Neutropenia (24%) and infections (13%) were the most common grade ≥3 AEs associated with ofatumumab maintenance. Ofatumumab maintenance is approved for patients with recurrent or progressive

Table 2.

Treatment Options for Relapsed/Refractory Therapy

Table 2.
CLL who are in CR or PR after ≥2 lines of prior treatment.

Assessment of Functional Status and Comorbidity

CLL/SLL is diagnosed mainly in older adults, with a median age at diagnosis of 72 years; approximately 70% of patients are diagnosed at age ≥65 years and 40% at age ≥75 years.32 Comorbidities are frequently present in older patients. In addition, organ function and bone marrow reserve decline with increasing age. CIRS, Charlson comorbidity index, and NCI comorbidity index are some of the scoring systems that can be used to assess comorbidities in patients with CLL. CIRS in combination with CrCl was used by the German CLL Study Group (GCLLSG) to assess the overall fitness of patients enrolled in clinical trials.33,34 In a study that assessed the comorbidity burden and investigated its impact on treatment in 555 patients with untreated CLL enrolled in 2 GCLLSG trials, 26% of patients had comorbidities involving the metabolic/endocrine system, 21% had comorbidities in vascular system, and 12% had cardiac comorbidities.33 The presence of multiple comorbidities (≥2 comorbidities) was an independent predictor of clinical outcome independent of patients' age or disease stage.33 The median OS (71.7 vs 90.2 months; P<.001) and PFS (21.0 vs 31.5 months; P<.01) were significantly shorter for patients with ≥2 comorbidities than for those with <2 comorbidities. These findings underscore the need to assess comorbidities, in addition to patient age and performance status (PS), before treatment selection. Older patients with adequate functional status can be treated with more active or intensive therapies,35 and should be evaluated for cytogenetic abnormalities using fluorescence in situ hybridization. Patient age and the presence or absence of del(17p) or TP53 mutations should then help direct treatment options, as discussed in the following section.

Treatment Recommendations

Early-stage disease in some patients may have an indolent course and in others may progress rapidly to advanced disease requiring immediate treatment. Patients with stage II–IV SLL, low-risk CLL (Rai stage 0; Binet A), or intermediate-risk CLL (Rai stage I–II; Binet B) may benefit from treatment if they become symptomatic or show evidence of progressive disease.36 Patients with advanced-stage or high-risk CLL (Rai stage III–IV; Binet C) with progressive cytopenia require treatment (see CSLL-3; page 295. Selected patients with mild, stable cytopenia may continue to be observed.

Absolute lymphocyte count alone is not an indication for treatment unless it is >200 to 300×109/L or symptoms related to leukostasis occur.36 Indications for initiating treatment include severe fatigue, weight loss, night sweats, and fever without infection; threatened end-organ function; progressive bulky disease (enlarged spleen or lymph nodes); progressive anemia or thrombocytopenia; or autoimmune anemia/thrombocytopenia unresponsive to corticosteroids.36 Asymptomatic patients should be observed until these indications become apparent. Recommendations for patients with indications for treatment are based on patient's age or functional status (comorbidity index/PS), as well as the presence or absence of del(17p) or TP53 mutations.

The age cutoff of 65 years is used in most clinical trials, including those conducted by the GCLLSG. In a retrospective analysis that evaluated the impact of age on outcome after initial treatment with different chemoimmunotherapy and chemotherapy regimens in patients with CLL enrolled in CALGB trials, the benefit of fludarabine compared with chlorambucil decreased marginally with age, with estimated hazard ratios of 0.70, 0.76, and 0.81 at 65, 70, and 75 years, respectively.37 The benefit of fludarabine relative to chlorambucil also decreased at an earlier age for OS than for PFS, with the estimated hazard ratios of 0.88, 1.01, and 1.15 at 65, 70, and 75 years, respectively. In addition, approximately 44% of patients aged >65 years have some degree of chronic kidney disease, which also increases the likelihood of toxicity associated with fludarabine-based regimens.38 Based on these data, the panel decided to change the age cutoff from 70 to 65 years.

CLL Without del(17p) or TP53 Mutations

First-Line Therapy: Obinutuzumab/chlorambucil (category 1),10,11 ibrutinib (category 1),16 and ofatumumab/chlorambucil12 are the preferred treatment options for frail patients with significant comorbidities (eg, not able to tolerate purine analogs) or patients aged ≥65 years and younger patients with significant comorbidities (see CSLL-5; page 297). Bendamustine with or without rituximab is a reasonable alternative for patients aged ≥65 years who are otherwise eligible for chemoimmunotherapy.6,7 In the CLL11 trial, there was a clinically meaningful improvement in PFS with a trend toward improved OS in patients treated with obinutuzumab/chlorambucil versus rituximab/chlorambucil.10,11 Therefore, rituximab/chlorambucil should be reserved for patients who cannot tolerate obinutuzumab.39,40

With multiple randomized studies showing a survival advantage for combination regimens containing chlorambucil or rituximab compared with monotherapy with either of these agents,10,12 most of the panel members acknowledged that monotherapy with chlorambucil or rituximab is not an effective first-line treatment even for frail patients with comorbid conditions. However, some panel members felt that given the favorable tolerability profile, monotherapy with rituximab or chlorambucil may be an appropriate treatment option for a small fraction of very frail patients or patients aged ≥65 years with substantial comorbidities or decreased PS for whom more intensive regimens are not appropriate.41,42 Rituximab and chlorambucil are included as alternate treatment options (category 3).

In patients aged <65 years without significant comorbidities, fludarabine-based chemoimmunotherapy has emerged as the standard of care, especially in those with mutated IGHV.4,5 Therefore, chemoimmunotherapy with FCR is the preferred treatment option (category 1) for these patients. FR, pentostatin/cyclophosphamide/rituximab (PCR), or bendamustine with or without rituximab are included as alternate options for chemoimmunotherapy.

The panel acknowledged that there are no data to support the inclusion of ibrutinib as a category 1 recommendation for patients aged <65 years, because the RESONATE-2 trial (on which the FDA based its approval of ibrutinib for first-line therapy in all patients with CLL/SLL) established the efficacy of ibrutinib as first-line therapy only in patients aged ≥65 years without del(17p).16 However, with the recent FDA approval, some panel members agreed that ibrutinib may be an appropriate option instead of chemoimmunotherapy in younger patients with unmutated IGHV who do want to enroll in a clinical trial. Therefore, the panel included ibrutinib as a category 2A recommendation for first-line therapy for patients aged <65 years without del(17p).

Relapsed or Refractory Therapy: Ibrutinib (category 1),18,19 idelalisib/rituximab (category 1),21 idelalisib,23 and venetoclax (particularly for patients deemed intolerant or refractory to ibrutinib or idelalisib)26 are included as preferred options for patients with relapsed or refractory disease, regardless of their age and comorbidities. The results of recent phase III trials have shown that the addition of idelalisib or ibrutinib to BR significantly improves PFS in patients with relapsed or refractory CLL.43,44 BR with idelalisib or ibrutinib is included an alternate option regardless of patient age and comorbidities.

For frail patients with significant comorbidities or patients aged ≥65 years and younger patients with comorbidities, reduced-dose FCR or PCR, bendamustine with or without rituximab, high-dose methylprednisolone (HDMP) or chlorambucil with rituximab, monotherapy with ofatumumab or obinutuzumab, lenalidomide or alemtuzumab with or without rituximab, or dose-dense rituximab are included as alternative options. For patients aged <65 years without significant comorbidities, chemoimmunotherapy (FCR, FC + ofatumumab, PCR, bendamustine ± rituximab, CHOP + rituximab, OFAR [oxaliplatin/fludarabine/cytarabine/rituximab]), monotherapy with ofatumumab or obinutuzumab, lenalidomide or alemtuzumab with or without rituximab, or HDMP with rituximab are included as alternate options.

Ofatumumab maintenance (category 2B) is recommended for patients who are in CR or PR as second-line therapy.31 Allogeneic hematopoietic cell transplant (HCT) can be considered for select patients (without significant comorbidities) after reinduction of remission.

CLL With del(17p) or TP53 Mutations

Enrollment in an appropriate clinical trial is recommended for patients with del(17p). In the absence of appropriate clinical trials, ibrutinib is the preferred treatment option for first-line therapy13,15; HDMP plus rituximab,45,46 obinutuzumab/chlorambucil,10 and alemtuzumab with or without rituximab4749 are included as alternate treatment options (see CSLL-D, 3 of 5; page 301). The efficacy of ibrutinib in del(17p) CLL/SLL exceeds the results of alternative regimens in the upfront and salvage settings, and should be considered the best choice in the absence of a contraindication.

Recent reports suggest that complex karyotype (≥3 unrelated chromosomal abnormalities in >1 cell on CpG-stimulated karyotype of CLL cells) is a stronger predictor of poor clinical outcomes than del(17p) in patients with relapsed or refractory CLL treated with ibrutinib-based regimens.50,51 In an analysis of 88 patients with relapsed or refractory CLL treated with ibrutinib-based regimens, in a multivariate analysis, only complex karyotype was significantly associated with inferior event-free survival (P=.006), whereas complex karyotype (P=.008) and fludarabine-refractory CLL (P=.005) were independently associated with inferior OS.51 Complex karyotype has also been identified as an independent prognostic factor for shorter time to first treatment.52 CpG-stimulated karyotyping is useful for identifying high-risk patients, particularly for treatment with ibrutinib.

Patients with response to first-line therapy should be considered for allogeneic HCT, if complex karyotype is present. However, available data suggest that complex karyotype (≥5 abnormalities) is associated with inferior OS and event-free survival after allogeneic SCT with reduced-intensity conditioning in patients with high-risk interphase cytogenetics.53 Allogeneic HCT is not recommended for patients with del(17p) CLL/SLL responding to first-line therapy with ibrutinib, if complex karyotype is not present. Ofatumumab maintenance (category 2B) is recommended for patients experiencing CR or PR to second-line therapy.31

Patients with no response to first-line therapy should be enrolled in clinical trials or be treated with second-line therapy for relapsed or refractory disease; preferred options for relapsed or refractory disease are ibrutinib,1820 venetoclax,25 idelalisib/rituximab,22 and idelalisib.23

Special Considerations for the Use of Small Molecule Inhibitors

Ibrutinib and idelalisib cause early mobilization of lymphocytes into the blood, resulting in a transient increase in absolute lymphocyte count in most patients, which does not signify disease progression.54,55 This onset of isolated lymphocytosis occurs during the first few weeks of ibrutinib treatment and may persist for several weeks on treatment. Although lymphocytosis can sometimes be profound, clinical consequence (ie, leukostasis) is extremely rare and treatment should be continued. Slow or incomplete resolution of lymphocytosis does not appear to impact outcome as measured by PFS (CSLL-F; pages 302 and 303).54

Atrial fibrillation (grade ≥3) and major hemorrhage (defined as serious or grade ≥3 bleeding events or central nervous system hemorrhage of any grade) have been reported in 6% and 4% of patients treated with ibrutinib, respectively.13,16 The benefit and risk of ibrutinib should be evaluated in patients requiring antiplatelet or anticoagulant therapies. Patients requiring warfarin have been excluded from clinical trials evaluating ibrutinib, and should not be given concomitantly with warfarin. Hypertension (grade ≥3) associated with ibrutinib (reported in 20%) has uncommonly been the basis for discontinuation and should be managed with antihypertensives as appropriate.13 Alternate treatment should be considered, especially in patients with hypertension that is not medically controllable. At the time of disease progression on ibrutinib, transition to alternate treatment should be performed as soon as possible upon stopping ibrutinib, because progression may accelerate when ibrutinib is stopped. Treatment-free interval should be as short as possible (CSLL-F; pages 302 and 303).

Fatal and/or serious hepatotoxicity, severe diarrhea or colitis, pneumonitis, and intestinal perforation have been observed in patients treated with idelalisib.56 Hepatotoxicity is a major concern in younger patients treated with idelalisib as first-line therapy.57 Close monitoring of transaminase levels is essential, and concurrent administration of idelalisib with other hepatotoxic drugs should be avoided. Idelalisib is also associated with opportunistic infections and febrile neutropenia. PJP and CMV reactivation have been reported in patients treated with idelalisib, and the risk of developing these opportunistic infections is highest in the first 6 months of treatment.43 The addition of CD20 monoclonal antibody or chemoimmunotherapy to idelalisib increases the risk of febrile neutropenia. Appropriate anti-infective prophylaxis and routine monitoring for early signs of infectious complications and CMV reactivation is recommended for patients receiving idelalisib (CSLL-F; pages 302 and 303).

Conclusions

The choice of first-line treatment for CLL/SLL should be based on disease stage, presence or absence of del(17p) or TPwent. Ibrutinib, idelalisib (± rituximab), and venetoclax are effective treatment options for relapsed or refractory del(17p) CLL/SLL. Careful monitoring of AEs after treatment initiation and supportive care for treatment-related complications should be an integral part of management of patients with CLL/SLL.

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